Our long-term goal is to greatly impact the management of dry eye (DE) by identifying novel preventive and therapeutic strategies for a disorder that negatively impacts the quality-of-life of one in five veterans. There is a growing appreciation from our work, and that of others, that some manifestations of ocular discomfort commonly described as symptoms of dry eye, are better understood as corneal pain. While DE symptoms were initially attributed to ocular surface dryness, it is now increasingly understood that some DE symptoms are associated with corneal nerve damage resembling the pathologic neuroplasticity of other neuropathic pain syndromes. In susceptible patients, these pathological changes, including peripheral sensitization, central sensitization, and altered descending modulation, may underlie certain persistent dry eye symptoms; and may explain the observed clinical heterogeneity in DE with frequent discordance between tear film measures and symptoms. Furthermore, we have shown that clinical descriptors of neuropathic pain (burning, sensitivity to light and wind) are correlated with severe and persistent DE symptoms, suggesting that dysfunction in the corneal somatosensory system may be an important but overlooked facet of some DE subtypes. To build upon our observations and address our goals we will undertake the following: Aim 1 will define DE subtypes and determine whether DE patients (334 cases) more frequently demonstrate clinical findings consistent with corneal and/or central sensitization compared to subjects without DE symptoms (167 controls) using a comprehensive advanced pain assessment protocol (cornea and cutaneous thresholds, temporal summation, conditioned pain modulation). Aim 2 will determine the relationship between ocular surface biomarkers of environmental stress and corneal injury (i.e., pro- and anti-inflammatory tear lipidome; MMP-9, osmolarity, serotonin) and our defined DE subtypes. In Aim 3, we will utilize state-of-the-art proprietary Pain Gene Exome Array technology to assess candidate genes implicated in DE; identify new genes and biologic pathways associated with susceptibility to DE subtypes; and attempt to replicate these findings using data from other previously genotyped persistent pain cohorts. These experiments will address a major gap in our current knowledge on DE. Our studies will advance our understanding of neuro-ophthalmologic pathology underlying DE subtypes; and greatly impact this field by facilitating more accurate diagnosis, prognosis, and mechanism- based therapeutic and preventive approaches for DE. Ultimately, these studies should decrease DE associated morbidity and improve the quality-of-life of veterans and non-veterans alike.